title: Mcl1 regulates the terminal mitosis of neural precursor cells in the mammalian brain through p27Kip1.
abstract: Cortical development requires the precise timing of neural precursor cell (NPC) terminal mitosis. Although cell cycle proteins regulate terminal mitosis, the factors that influence the cell cycle machinery are incompletely understood. Here we show in mice that myeloid cell leukemia 1 (Mcl1), an anti-apoptotic Bcl-2 protein required for the survival of NPCs, also regulates their terminal differentiation through the cell cycle regulator p27(Kip1). A BrdU-Ki67 cell profiling assay revealed that in utero electroporation of Mcl1 into NPCs in the embryonic neocortex increased NPC cell cycle exit (the leaving fraction). This was further supported by a decrease in proliferating NPCs (Pax6(+) radial glial cells and Tbr2(+) neural progenitors) and an increase in differentiating cells (Dcx(+) neuroblasts and Tbr1(+) neurons). Similarly, BrdU birth dating demonstrated that Mcl1 promotes premature NPC terminal mitosis giving rise to neurons of the deeper cortical layers, confirming their earlier birthdate. Changes in Mcl1 expression within NPCs caused concomitant changes in the levels of p27(Kip1) protein, a key regulator of NPC differentiation. Furthermore, in the absence of p27(Kip1), Mcl1 failed to induce NPC cell cycle exit, demonstrating that p27(Kip1) is required for Mcl1-mediated NPC terminal mitosis. In summary, we have identified a novel physiological role for anti-apoptotic Mcl1 in regulating NPC terminal differentiation.
authors.affiliation: Division of BioMedical Sciences, Memorial University, 300 Prince Philip Drive, St John's, NL A1B 3V6, Canada.
authors.forename: S M Mahmudul
authors.initials: SM
authors.lastname: Hasan
authors.forename: Ashley D
authors.initials: AD
authors.lastname: Sheen
authors.forename: Angela M
authors.initials: AM
authors.lastname: Power
authors.forename: Lisa Marie
authors.initials: LM
authors.lastname: Langevin
authors.forename: Jieying
authors.initials: J
authors.lastname: Xiong
authors.forename: Michael
authors.initials: M
authors.lastname: Furlong
authors.forename: Kristine
authors.initials: K
authors.lastname: Day
authors.forename: Carol
authors.initials: C
authors.lastname: Schuurmans
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Opferman
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Vanderluit
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000089662:Doublecortin Protein; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008938:Mitosis; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis; D011247:Pregnancy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C493961:Cdkn1b protein, mouse; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: Bcl-2; Cdkn1b; Cell cycle; Mcl-1; Mouse; Neurogenesis